Cargando…

Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B

The HSP90/CDC37 chaperone system not only assists the maturation of many protein kinases but also maintains their structural integrity after folding. The interaction of mature kinases with the HSP90/CDC37 complex is governed by the conformational stability of the catalytic domain, while the initial...

Descripción completa

Detalles Bibliográficos
Autores principales: Papenfuss, Marco, Lützow, Svenja, Wilms, Gerrit, Babendreyer, Aaron, Flaßhoff, Maren, Kunick, Conrad, Becker, Walter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844047/
https://www.ncbi.nlm.nih.gov/pubmed/35165364
http://dx.doi.org/10.1038/s41598-022-06423-0
_version_ 1784651398968770560
author Papenfuss, Marco
Lützow, Svenja
Wilms, Gerrit
Babendreyer, Aaron
Flaßhoff, Maren
Kunick, Conrad
Becker, Walter
author_facet Papenfuss, Marco
Lützow, Svenja
Wilms, Gerrit
Babendreyer, Aaron
Flaßhoff, Maren
Kunick, Conrad
Becker, Walter
author_sort Papenfuss, Marco
collection PubMed
description The HSP90/CDC37 chaperone system not only assists the maturation of many protein kinases but also maintains their structural integrity after folding. The interaction of mature kinases with the HSP90/CDC37 complex is governed by the conformational stability of the catalytic domain, while the initial folding of the protein kinase domain is mechanistically less well characterized. DYRK1A (Dual-specificity tyrosine (Y)-phosphorylation Regulated protein Kinase 1A) and DYRK1B are closely related protein kinases with discordant HSP90 client status. DYRK kinases stoichiometrically autophosphorylate on a tyrosine residue immediately after folding, which served us as a traceable marker of successful maturation. In the present study, we used bacterial expression systems to compare the capacity of autonomous maturation of DYRK1A and DYRK1B in the absence of eukaryotic cofactors or chaperones. Under these conditions, autophosphorylation of human DYRK1B was severely compromised when compared with DYRK1A or DYRK1B orthologs from zebrafish and Xenopus. Maturation of human DYRK1B could be restored by bacterial expression at lower temperatures, suggesting that folding was not absolutely dependent on eukaryotic chaperones. The differential folding properties of DYRK1A and DYRK1B were largely due to divergent sequences of the C-terminal lobes of the catalytic domain. Furthermore, the mature kinase domain of DYRK1B featured lower thermal stability than that of DYRK1A when exposed to heat challenge in vitro or in living cells. In summary, our study enhances the mechanistic understanding of the differential thermodynamic properties of two closely related protein kinases during initial folding and as mature kinases.
format Online
Article
Text
id pubmed-8844047
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-88440472022-02-16 Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B Papenfuss, Marco Lützow, Svenja Wilms, Gerrit Babendreyer, Aaron Flaßhoff, Maren Kunick, Conrad Becker, Walter Sci Rep Article The HSP90/CDC37 chaperone system not only assists the maturation of many protein kinases but also maintains their structural integrity after folding. The interaction of mature kinases with the HSP90/CDC37 complex is governed by the conformational stability of the catalytic domain, while the initial folding of the protein kinase domain is mechanistically less well characterized. DYRK1A (Dual-specificity tyrosine (Y)-phosphorylation Regulated protein Kinase 1A) and DYRK1B are closely related protein kinases with discordant HSP90 client status. DYRK kinases stoichiometrically autophosphorylate on a tyrosine residue immediately after folding, which served us as a traceable marker of successful maturation. In the present study, we used bacterial expression systems to compare the capacity of autonomous maturation of DYRK1A and DYRK1B in the absence of eukaryotic cofactors or chaperones. Under these conditions, autophosphorylation of human DYRK1B was severely compromised when compared with DYRK1A or DYRK1B orthologs from zebrafish and Xenopus. Maturation of human DYRK1B could be restored by bacterial expression at lower temperatures, suggesting that folding was not absolutely dependent on eukaryotic chaperones. The differential folding properties of DYRK1A and DYRK1B were largely due to divergent sequences of the C-terminal lobes of the catalytic domain. Furthermore, the mature kinase domain of DYRK1B featured lower thermal stability than that of DYRK1A when exposed to heat challenge in vitro or in living cells. In summary, our study enhances the mechanistic understanding of the differential thermodynamic properties of two closely related protein kinases during initial folding and as mature kinases. Nature Publishing Group UK 2022-02-14 /pmc/articles/PMC8844047/ /pubmed/35165364 http://dx.doi.org/10.1038/s41598-022-06423-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Papenfuss, Marco
Lützow, Svenja
Wilms, Gerrit
Babendreyer, Aaron
Flaßhoff, Maren
Kunick, Conrad
Becker, Walter
Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title_full Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title_fullStr Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title_full_unstemmed Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title_short Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B
title_sort differential maturation and chaperone dependence of the paralogous protein kinases dyrk1a and dyrk1b
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844047/
https://www.ncbi.nlm.nih.gov/pubmed/35165364
http://dx.doi.org/10.1038/s41598-022-06423-0
work_keys_str_mv AT papenfussmarco differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT lutzowsvenja differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT wilmsgerrit differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT babendreyeraaron differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT flaßhoffmaren differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT kunickconrad differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b
AT beckerwalter differentialmaturationandchaperonedependenceoftheparalogousproteinkinasesdyrk1aanddyrk1b